Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.

227 words 23 Article Body: 3771 words (excluding M&M, legends, abstract and references) 24 Fig.: 8 25 Tables: 0 26 Supplementary Information: 1 27 28 2 Abstract 29 Imbalance of neuronal proteostasis associated with misfolding and aggregation of Tau protein is a 30 common neurodegenerative feature in Alzheimer's disease (AD) and other Tauopathies. Consistent 31with suggestions that lifetime stress may be an important AD precipitating factor, we previously 32 reported that environmental stress and high glucocorticoid (GC) levels induce accumulation of 33 aggregated Tau; however, the molecular mechanisms for such process remain unclear. Herein, we 34 monitor a novel interplay between RNA-binding proteins (RBPs) and autophagic machinery in the 35 underlying mechanisms through which chronic stress and high GC levels impact on Tau proteostasis 36 precipitating Tau aggregation. Using molecular, pharmacological and behavioral analysis, we 37 demonstrate that chronic stress and high GC trigger a mTOR-dependent inhibition of autophagy, 38 leading to accumulation of Tau aggregates and cell death in P301L-Tau expressing mice and cells. 39In parallel, we found that environmental stress and GC disturb cellular homeostasis and trigger the 40 insoluble accumulation of different RBPs, such as PABP, G3BP1, TIA-1, and FUS, shown to form 41 Stress granules(SGs) and Tau aggregation. Interestingly, an mTOR-driven pharmacological 42 stimulation of autophagy attenuates the GC-driven accumulation of Tau and SG-related proteins as 43 well as the related cell death, suggesting a critical interface between autophagy and the response of 44 the SG-related protein in the neurodegenerative potential of chronic stress and GC. These studies 45 provide novel insights into the RNA-protein intracellular signaling regulating the precipitating role of 46 environmental stress and GC on Tau-driven brain pathology. 47 48 49 50 51 Silva et al 3 Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a complex 53 pathophysiology and still undefined initiators. Several risk factors have been associated with AD 54 pathology, with recent evidence supporting a detrimental role of lifetime stress 1-3 . Clinical studies 55 relate distress, high cortisol levels and dysfunction of hypothalamus-pituitary-adrenal (HPA) axis with 56 poor memory scores and earlier disease onset in AD patients highlighting the potential implication of 57 chronic stress and glucocorticoids (GC) in the pathogenesis and/or progression of the disorder 4-6 . In 58 line with the above clinical evidence, experimental studies have shown that chronic stress and 59 exposure to high GC levels trigger Tau hyperphosphorylation and malfunction leading to its 60 accumulation, formation of neurotoxic Tau aggregates and AD pathology 1,7,8 . Despite our little 61knowledge about the molecular mechanisms that underpin stress-driven pathology, experimental 62 evidence suggests that stress/GC reduces Tau turnover 9 , suggesting that stress/GC impact on the 63 chaperones and proteases th...

words)Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD, and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endo-lysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery.Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAVmediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.

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Type 2 diabetes increases the risk for dementia, including Alzheimer’s disease (AD). Pioglitazone (Pio), a pharmacological agonist of the peroxisome proliferator-activated receptor γ (PPARγ), improves insulin sensitivity and has been suggested to have potential in the management of AD symptoms, albeit through mostly unknown mechanisms. We here investigated the potential of Pio to counter synaptic malfunction and loss, a characteristic of AD pathology and its accompanying cognitive deficits. Results from experiments on primary mouse neuronal cultures and a human neural cell line (SH-SY5Y) show that Pio treatment attenuates amyloid β (Aβ)-triggered the pathological (mis-) processing of amyloid precursor protein (APP) and inhibits Aβ-induced accumulation and hyperphosphorylation of Tau. These events are accompanied by increased glutamatergic receptor 2B subunit (GluN2B) levels that are causally linked with neuronal death. Further, Pio treatment blocks Aβ-triggered missorting of hyperphosphorylated Tau to synapses and the subsequent loss of PSD95-positive synapses. These latter effects of Pio are PPARγ-mediated since they are blocked in the presence of GW9662, a selective PPARγ inhibitor. Collectively, these data show that activated PPARγ buffer neurons against APP misprocessing, Tau hyperphosphorylation and its missorting to synapses and subsequently, synaptic loss. These first insights into the mechanisms through which PPARγ influences synaptic loss make a case for further exploration of the potential usefulness of PPARγ agonists in the prevention and treatment of synaptic pathology in AD.